Compounds in the treatment of dementia related diseases, Alzheimer&#39;s Disease and conditions associated with glycogen synthase kinase-3

ABSTRACT

The present invention relates to new compounds of formula I wherein R 1 , R 2 , R 3 , n, m are defined as in claim 1, a process for their preparation and new intermediates used in the preparation thereof, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy, especially in the prevention and/or treatment of dementia related diseases, Alzheimer&#39;s Disease and conditions associated with glycogen synthase kinase-3

This application is a 371 of PCT/SE02/02371, filed on Dec. 18, 2002,which claims the benefit of the Provisional Application No. 60/344,885,filed on Dec. 21, 2001.

FIELD OF THE INVENTION

The present invention relates to new compounds of formula I, as a freebase or salts thereof, to pharmaceutical formulations containing saidcompounds and to the use of said compounds in therapy. The presentinvention further relates to processes for the preparation of compoundsof formula I and to new intermediates used in the preparation thereof.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase 3 (GSK3) is a serine/threonine protein kinasecomposed of two isoforms (α and β), which are encoded by distinct genesbut are highly homologous within the catalytic domain. GSK3 is highlyexpressed in the central and peripheral nervous system. GSK3phosphorylates several substrates including tau, β-catenin, glycogensynthase, pyruvate dehydrogenase and elongation initiation factor 2b(eEF2b). Insulin and growth factors activate protein kinase B, whichphosphorylates GSK3 on serine 9 the residue and inactivates it.

Alzheimer's Disease (AD) Dementias, and Taupathies.

AD is characterized by cognitive decline, cholinergic dysfunction andneuronal death, neurofibrillary tangles and senile plaques consisting ofamyloid-β deposits. The sequence of these events in AD is unclear, butbelieved to be related. Glycogen synthase kinase 3β (GSK3β) or Tau (τ)phosphorylating kinase selectively phosphorylates the microtubuleassociated protein τ in neurons at sites that are hyperphosphorylated inAD brains. Hyperphosphorylated protein τ has lower affinity formicrotubules and accumulates as paired helical filaments, which are themain components that constitute neurofibrillary tangles and neuropilthreads in AD brains. This results in depolymerization of microtubules,which leads to dying back of axons and neuritic dystrophy.Neurofibrillary tangles are consistently found in diseases such as AD,amyotrophic lateral sclerosis, parkinsonism-dementia complex of Gaum,corticobasal degeneration, dementia pugilistica and head trauma, Down'ssyndrome, postencephalatic parkinsonism, progressive supranuclear palsy,Niemann-Pick's Disease and Pick's Disease. Addition of amyloid-β toprimary hippocampal cultures results in hyperphosphorylation of τ and apaired helical filaments-like state via induction of GSK3β activity,followed by disruption of axonal transport and neuronal death (Imahoriand Uchida, J. Biochem 121:179-188, 1997). GSK3β preferentially labelsneurofibrillary tangles and has been shown to be active in pre-tangleneurons in AD brains. GSK3 protein levels are also increased by 50% inbrain tissue from AD patients. Furthermore, GSK3β phosphorylatespyruvate dehydrogenase, a key enzyme in the glycolytic pathway andprevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS93:2719-2723, 1996). Acetyl-Co-A is critical for the synthesis ofacetylcholine, a neurotransmitter with cognitive functions. Thus, GSK3βinhibition may have beneficial effects in progression as well as thecognitive deficits associated with Alzheimer's disease and otherabove-referred to diseases.

Chronic and Acute Neurodegenerative Diseases.

Growth factor mediated activation of the PI3K/Akt pathway has been shownto play a key role in neuronal survival. The activation of this pathwayresults in GSK3β inhibition. Recent studies (Bhat et. al., PNAS97:11074-11079 (2000)) indicate that GSK3β activity is increased incellular and animal models of neurodegeneration such as cerebralischemia or after growth factor deprivation. For example, the activesite phosphorylation was increased in neurons vulnerable to apoptosis, atype of cell death commonly thought to occur in chronic and acutedegenerative diseases such as Alzheimer's Disease, Parkinson's Disease,amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia,ischemic stroke and head trauma. Lithium was neuroprotective ininhibiting apoptosis in cells and in the brain at doses that resulted inthe inhibition of GSK3β. Thus GSK3β inhibitors could be useful inattenuating the course of neurodegenerative diseases.

Bipolar Disorders (BD)

Bipolar Disorders are characterised by manic episodes and depressiveepisodes. Lithium has been used to treat BD based on its moodstabilising effects. The disadvantage of lithium is the narrowtherapeutic window and the danger of overdosing that can lead to lithiumintoxication. The recent discovery that lithium inhibits GSK3 attherapeutic concentrations has raised the possibility that this enzymerepresents a key target of lithium's action in the brain (Stambolic etal., Curr. Biol. 6:1664-1668, 1996; Klein and Melton; PNAS 93:8455-8459,1996). Inhibition of GSK3β may therefore be of therapeutic relevance inthe treatment of BD as well as in AD patients that have affectivedisorders.

Schizophrenia

GSK3 is involved in signal transduction cascades of multiple cellularprocesses, particularly during neural development. Kozlovsky et al (Am JPsychiatry 2000 May; 157(5):831-3) found that GSK3β levels were 41%lower in the schizophrenic patients than in comparison subjects. Thisstudy indicates that schizophrenia involves neurodevelopmental pathologyand that abnormal GSK3 regulation could play a role in schizophrenia.Furthermore, reduced β-catenin levels have been reported in patientsexhibiting schizophrenia (Cotter et al., Neuroreport 9:1379-1383(1998)).

Diabetes

Insulin stimulates glycogen synthesis in skeletal muscles via thedephosphorylation and thus activation of glycogen synthase. Underresting conditions, GSK3 phosphorylates and inactivates glycogensynthase via dephosphorylation. GSK3 is also over-expressed in musclesfrom Type II diabetic patients (Nikoulina et al., Diabetes 2000February; 49(2):263-71). Inhibition of GSK3 increases the activity ofglycogen synthase thereby decreasing glucose levels by its conversion toglycogen. GSK3 inhibition may therefore be of therapeutic relevance inthe treatment of Type I and Type II diabetes and diabetic neuropathy.

Hair Loss

GSK3 phosphorylates and degrades β-catenin. β-catenin is an effector ofthe pathway for keratonin synthesis. β-catenin stabilisation may be leadto increase hair development. Mice expressing a stabilised β-catenin bymutation of sites phosphorylated by GSK3 undergo a process resembling denovo hair morphogenesis (Gat et al., Cell 1998 Nov. 25;95 (5):605-14)).The new follicles formed sebaceous glands and dermal papilla, normallyestablished only in embryogenesis. Thus GSK3 inhibition may offertreatment for baldness.

Oral Contraceptives

Vijajaraghavan et al. (Biol Reprod 2000 June; 62 (6):1647-54) reportedthat GSK3 is high in motile versus immotile sperm. Immunocytochemistryrevealed that GSK3 is present in the flagellum and the anterior portionof the sperm head. These data suggest that GSK3 could be a key elementunderlying motility initiation in the epididymis and regulation ofmature sperm function. Inhibitors of GSK3 could be useful ascontraceptives for males.

DISCLOSURE OF THE INVENTION

The object of the present invention is to provide compounds having aselective inhibiting effect at GSK3 as well as having a goodbioavailability.

Accordingly, the present invention provides a compound of formula I:

wherein:

-   R¹ is hydrogen;-   R² is carboxy, C₂₋₆alkoxycarbonyl, fluoromethyl, difluoromethyl,    fluoromethoxy, difluoromethoxy, trifluoromethoxy, or a group R⁴X¹,    -   wherein X¹ is C₂₋₄alkanoyl, CONR⁵R⁶, SO₂NR⁷R⁸ or SO₂R⁹ (wherein        R⁵ and R⁷ each independently are hydrogen or C₁₋₂alkyl and R⁶,        R⁸ and R⁹ each independently are C₁₋₄alkyl or a bond and wherein        R⁴ is linked to R⁶, R⁸ and R⁹); and    -   R⁴ is NR^(A)R^(B), OR^(A), CH(OC₁₋₆alkyl)₂, or a 7 membered        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which heterocyclic group may be        saturated or unsaturated and which heterocyclic group may be        substituted with one or two substituents selected independently        from hydroxy, oxo, halogeno, C₁₋₃alkyl, C₃₋₆cycloalkyl,        C₁₋₃alkoxy, C₁₋₃alkanoyloxy, C₁₋₃alkylOH, C₁₋₃alkylphenyl,        carbamoyl, N—C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl,        aminosulphonyl, N—C₁₋₄alkylaminosulphonyl,        N,N-di(C₁₋₄alkyl)aminosulphonyl, trifluoromethyl, cyano, amino,        nitro and C₁₋₄alkoxycarbonyl, and said 7 membered heterocyclic        group may optionally be fused with a 5 or 6 membered saturated        or unsaturated ring containing atoms selected independently from        C, N, O or S, which may be substituted with one or two        substituents selected independently from hydroxy, oxo, halogeno,        trifluoromethyl, C₁₋₃alkyl, C₃₋₆cycloalkyl, C₁₋₃alkoxy, cyano,        amino and nitro; or    -   R⁴ is a phenyl or a 5 or 6 membered heterocyclic group with one        or two heteroatoms selected independently from O, S and N, which        heterocyclic group may be saturated or unsaturated and which        phenyl or heterocyclic group may be substituted with one or two        substituents selected independently from oxo, C₃₋₆cycloalkyl,        C₁₋₃alkylOH, C₁₋₃alkylphenyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,        N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,        N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;        or    -   R⁴ is phenyl or a 5 or 6 membered heterocyclic group with one or        two heteroatoms selected independently from O, S and N, which        heterocyclic group may be saturated or unsaturated and which        phenyl or heterocyclic group may be substituted with one or two        substituents selected independently from hydroxy, oxo, halogeno,        C₁₋₃alkyl, C₃₋₆cycloalkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,        C₁₋₃alkylOH, C₁₋₃alkylphenyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,        N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,        N—C₁₋₄alkylaminosulphonyl, N,N-di(C₁₋₄alkyl)aminosulphonyl,        trifluoromethyl, cyano, amino, nitro and C₁₋₄alkoxycarbonyl, and        said phenyl or 5 or 6 membered heterocyclic group is fused with        a 5 or 6 membered saturated or unsaturated ring containing atoms        selected independently from C, N, O or S, which may be        substituted with one or two substituents selected independently        from hydroxy, oxo, halogeno, trifluoromethyl, C₁₋₃alkyl,        C₃₋₆cycloalky), C₁₋₃alkoxy, cyano, amino and nitro; and    -   R^(A) and R^(B) are selected independently from hydrogen,        C₁₋₆alkyl, phenyl and benzyl;-   R³ is hydroxy, halogeno, nitro, fluoromethyl, difluoromethyl,    trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy,    2,2,2-trifluoroethyl, C₁₋₃alkyl, cyano, amino or R¹⁰X²,    -   wherein X² is O, CH₂, S, SO, SO₂, NR¹¹CO, CONR¹², SO₂NR¹³,        NR¹⁴SO₂ or NR¹⁵ (wherein R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl),        or X² is a direct bond; and    -   R¹⁰ is selected from one of the following groups:    -   1) hydrogen or C₂₋₅alkyl which may be substituted with one or        more groups selected independently from hydroxy, fluoro and        amino;    -   2) C₁₋₅alkylX³COR¹⁶ (wherein X³ is O or NR¹⁷ (wherein R¹⁷ is        hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl) and R¹⁶ is        C₁₋₃alkyl, NR¹⁸R¹⁹ or OR²⁰ (wherein R¹⁸, R¹⁹ and R²⁰ each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl));    -   3) C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O, S, SO, SO₂, OCO, NR²²CO,        CONR²³, SO₂NR ²⁴, NR²⁵SO₂ or NR²⁶ (wherein R²², R²³, R²⁴, R²⁵        and R²⁶ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R²¹ is hydrogen, C₁₋₃alkyl,        cyclopentyl, cyclohexyl or a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which C₁₋₃alkyl group may be        substituted with one or two substituents selected independently        from oxo, hydroxy, halogeno and C₁₋₄alkoxy and which        heterocyclic group may be substituted with one or two        substituents selected independently from oxo, hydroxy, halogeno,        C₁₋₄alkyl, C₁₋₄hydroxyalkyl and C₁₋₄alkoxy);    -   4) C₁₋₅alkylX⁵C₁₋₅alkylX⁶R²⁷ (wherein X⁵ and X⁶ each        independently are O, S, SO, SO₂, NR²⁸CO, CONR²⁹, SO₂NR³⁰,        NR³¹SO₂ or NR³² (wherein R²⁸, R²⁹, R³⁰, R³¹ and R³² each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl)        and R²⁷ is hydrogen or C₁₋₃alkyl);    -   5) C₁₋₅alkylR³³ (wherein R³³ is a 5 or 6 membered saturated        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which C₁₋₅alkyl or heterocyclic        group may be substituted with one or two substituents selected        independently from oxo, hydroxy, halogeno, C₁₋₄alkyl,        C₁₋₄hydroxyalkyl, C₂₋₄alkanoyl and C₁₋₄alkoxy);    -   6) C₂₋₅alkenylR³³ (wherein R³³ is as defined hereinbefore);    -   7) C₂₋₅alkynylR³³ (wherein R³³ is as defined hereinbefore);    -   8) R³⁴ (wherein R³⁴ is a pyridone group, a phenyl group or a 5        or 6 membered aromatic heterocyclic group with 1 to 3        heteroatoms selected independently from O, N and S, which        pyridone, phenyl or heterocyclic group may carry up to 5        substituents selected independently from hydroxy, halogeno,        amino, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄hydroxyalkyl, C₁₋₄aminoalkyl,        C₁₋₄alkylamino, C₁₋₄hydroxyalkoxy, carboxy, cyano, CONR³⁵R³⁶ and        NR³⁷COR³⁸ (wherein R³⁵, R³⁶, R³⁷ and R³⁸ each independently are        hydrogen, C₁₋₄alkyl or C₁₋₃alkoxyC₂₋₃alkyl));    -   9) C₁₋₅alkylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   10) C₂₋₅alkenylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   11) C₂₋₅alkynylR³⁴ (wherein R³⁴ is as defined hereinbefore);    -   12) C₁₋₅alkylX⁷R³⁴ (wherein X⁷ is O, S, SO, SO₂, NR³⁹CO, CONR⁴⁰,        SO₂NR⁴¹ , NR⁴²SO₂ or NR⁴³ (wherein R³⁹, R⁴⁰, R⁴¹, R⁴² and R⁴³        each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   13) C₂₋₅alkenylX⁸R³⁴ (wherein X⁸ is O, S, SO, SO₂, NR⁴⁴CO,        CONR⁴⁵, SO₂NR⁴⁶, NR⁴⁷SO₂ or NR⁴⁸ (wherein R⁴¹, R⁴⁵, R⁴⁶, R⁴⁷ and        R⁴⁸ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   14) C₂₋₅alkynylX⁹R³⁴ (wherein X⁹ is O, S, SO, SO₂, NR⁴⁹CO,        CONR⁵⁰, SO₂NR⁵¹, NR⁵²SO₂ or NR⁵³ (wherein R⁴⁹, R⁵⁰, R⁵¹, R⁵² and        R⁵³ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore); and    -   15) C₁₋₃alkylX¹⁰C₁₋₃alkylR³⁴ (wherein X¹⁰ is O, S, SO, SO₂,        NR⁵⁴CO, ONR⁵⁵, SO₂NR⁵⁶, NR⁵⁷SO₂ or NR⁵⁸ (wherein R⁵⁴, R⁵⁵, R⁵⁶,        R⁵⁷ and R⁵⁸ each independently are hydrogen, C₁₋₃alkyl or        C₁₋₃alkoxyC₂₋₃alkyl) and R³⁴ is as defined hereinbefore);    -   16) R³³ (wherein R³³ is as defined hereinbefore); and    -   17) C₁₋₃alkylX¹⁰C₁₋₃alkylR³³ (wherein X¹⁰ and R³³ are as defined        hereinbefore));-   n is 1, 2, 3 or 4;-   m is 1, 2, 3 or 4;-   as a free base or salts thereof.

One aspect of the invention relates to compounds of formula I, whereinR² is carboxy, fluoromethyl, difluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, or a group R⁴X¹,

-   -   wherein X¹ is C₂₋₄alkanoyl, CONR⁵R⁶, SO₂NR⁷R⁸ or SO₂R⁹ (wherein        R⁵ and R⁷ each independently are hydrogen or C₁₋₂alkyl and R⁶,        R⁸ and R⁹ each independently are C₁₋₄alkyl or a bond and wherein        R⁴ is linked to R⁶, R⁸ and R⁹); and    -   R⁴ is NR^(A)R^(B), OR^(A), CH(OC₁₋₆alkyl)₂, or a 7 membered        heterocyclic group with one or two heteroatoms selected        independently from O, S and N, which heterocyclic group may be        saturated or unsaturated and which heterocyclic group may be        substituted with one or two substituents selected independently        from hydroxy, oxo, halogeno, C₁₋₃alkyl, C₃₋₆cycloalkyl,        C₁₋₃alkoxy, C₁₋₃alkanoyloxy, C₁₋₃alkylOH, C₁₋₃alkylphenyl,        carbamoyl, N—C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl,        aminosulphonyl, N—C₁₋₄alkylaminosulphonyl,        N,N-di(C₁₋₄alkyl)aminosulphonyl, trifluoromethyl, cyano, amino,        nitro and C₁₋₄alkoxycarbonyl, and said 7 membered heterocyclic        group may optionally be fused with a 5 or 6 membered saturated        or unsaturated ring containing atoms selected independently from        C, N, O or S, which may be substituted with one or two        substituents selected independently from hydroxy, oxo, halogeno,        trifluoromethyl, C₁₋₃alkyl, C₃₋₆cycloalkyl, C₁₋₃alkoxy, cyano,        amino and nitro; or    -   R⁴ is a phenyl or a 5 or 6 membered heterocyclic group with one        or two heteroatoms selected independently from O, S and N, which        heterocyclic group may be saturated or unsaturated and which        phenyl or heterocyclic group may be substituted with one or two        substituents selected independently from oxo, C₃₋₆cycloalkyl,        C₁₋₃alkylOH, C₁₋₃alkylphenyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,        N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,        N—C₁₋₄alkylaminosulphonyl and N,N-di(C₁₋₄alkyl)aminosulphonyl;        or    -   R⁴ is phenyl or a 5 or 6 membered heterocyclic group with one or        two heteroatoms selected independently from O, S and N, which        heterocyclic group may be saturated or unsaturated and which        phenyl or heterocyclic group may be substituted with one or two        substituents selected independently from hydroxy, oxo, halogeno,        C₁₋₃alkyl, C₃₋₆cycloalkyl, C₁₋₃alkoxy, C₁₋₃alkanoyloxy,        C₁₋₃alkylOH, C₁₋₃alkylphenyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,        N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,        N—C₁₋₄alkylaminosulphonyl, N,N-di(C₁₋₄alkyl)aminosulphonyl, tri        fluoromethyl, cyano, amino, nitro and C₁₋₄alkoxycarbonyl, and        said phenyl or 5 or 6 membered heterocyclic group is fused with        a 5 or 6 membered saturated or unsaturated ring containing atoms        selected independently from C, N, O or S, which may be        substituted with one or two substituents selected independently        from hydroxy, oxo, halogeno, trifluoromethyl, C₁₋₃alkyl,        C₃₋₆cycloalkyl, C₁₋₃alkoxy, cyano, amino and nitro; and        R^(A) and R^(B) are selected independently from hydrogen,        C₁₋₆alkyl, phenyl and benzyl.

In another aspect of the invention R² is carboxy or C₂₋₆alkoxycarbonyl.

In a third aspect of the invention X¹ is CONR⁵R⁶ (wherein R⁵ is hydrogenor C₁₋₂alkyl and R⁶ is C₁₋₄alkyl or a bond and wherein R⁴ is linked toR⁶).

In yet another aspect of the invention R⁴ is NR^(A)R^(B), OR^(A),CH(OC₁₋₆alkyl)₂, or a 7 membered heterocyclic group with one or twoheteroatoms selected independently from O, S and N, which heterocyclicgroup may be saturated or unsaturated and which heterocyclic group maybe substituted with one or two substituents selected independently fromhydroxy, oxo, halogeno, C₁₋₃alkyl, C₃₋₆cycloalkyl, C₁₋₃alkoxy,C₁₋₃alkanoyloxy, C₁₋₃alkylOH, C₁₋₃alkylphenyl, carbamoyl,N—C₁₋₄alkylcarbamoyl, N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl,N—C₁₋₄alkylaminosulphonyl, N,N-di(C₁₋₄alkyl)aminosulphonyl,trifluoromethyl, cyano, amino, nitro and C₁₋₄alkoxycarbonyl;

R^(A) and R^(B) are selected independently from hydrogen, C₁₋₆alkyl andphenyl.

In a further aspect of the R⁴ is phenyl or a 5 or 6 memberedheterocyclic group with one or two heteroatoms selected independentlyfrom O and N, which heterocyclic group may be saturated or unsaturatedand which phenyl or heterocyclic group may be substituted with one ortwo substituents selected independently from oxo, C₃₋₆cycloalkyl,C₁₋₃alkylOH, C₁₋₃alkylphenyl, carbamoyl, N—C₁₋₄alkylcarbamoyl,N,N-di(C₁₋₄alkyl)carbamoyl, aminosulphonyl, N—C, alkylaminosulphonyl andN,N-di(C₁₋₄alkyl)aminosulphonyl.

In yet another aspect of the invention R⁴ is phenyl or a 5 or 6 memberedheterocyclic group with one or two heteroatoms selected independentlyfrom O, S and N, which heterocyclic group may be saturated orunsaturated, and said phenyl or 5 or 6 membered heterocyclic group isfused with a 5 or 6 membered saturated or unsaturated ring containingatoms selected independently from C, N, O or S, which may be substitutedwith one or two substituents selected independently from hydroxy, oxo,halogeno, trifluoromethyl, C₁₋₃alkyl, C₃₋₆cycloalkyl, C₁₋₃alkoxy, cyano,amino and nitro.

In another aspect of the invention R³ is R¹⁰X²,

-   -   wherein X² is O; and    -   R¹⁰ is C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O or NR²⁶ (wherein R²¹ and        R²⁶ independently are hydrogen, C₁₋₃alkyl, cyclopentyl or        cyclohexyl)); and        m is 1 or 2.

One aspect of the present invention relates to compounds having at leastone R² and at least one R³ substituent, wherein R³ represents an esterand R² is as defined above.

The present invention further relates to compounds of general formula I,wherein the R² is substituted on position 5 and/or 6 and R³ issubstituted on position 6, 7 and/or 8.

In a further aspect of the invention the following compounds areprovided:

-   3-[7-2(-Methoxyethoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic    acid (2-oxoazepan-3-yl)amide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid[3-(methylphenylamino)propyl]amide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid [3-(1-hydroxyethyl)phenyl]amide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid (4-cyclohexylphenyl)amide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid (4,4-diethoxybutyl)amide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid (1H-benzoimidazol-2-ylmethyl)amide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid [2-(5-methyl-1H-indol-3-yl)ethyl]amide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid 4-sulfamoylbenzylamide,-   2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylic    acid (1-benzylpiperidin-4-yl)amide,    as a free base or salts thereof.

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’ or ‘definedhereinbefore’ the said group encompasses the first occurring andbroadest definition as well as each and all of the preferred definitionsof that group.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₆’ means a carbon group having 1, 2, 3, 4, 5 or 6carbon atoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups C₁₋₆alkyl may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl.

In this specification, unless stated otherwise, the term“C₃₋₆cycloalkyl” includes cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

The term “alkoxy” as used herein, unless stated otherwise includes“alkyl”O groups in which “alkyl” is as hereinbefore defined. C₁₋₆alkoxymay be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy,neo-pentyloxy, n-hexyloxy or i-hexyloxy.

The term “alkanoyl” as used herein, unless otherwise stated includesformyl and alkylC═O groups in which “alkyl” is as defined hereinbefore,for example C₂alkanoyl is ethanoyl and refers to CH₃C═O, C₁alkanoyl isformyl and refers to CHO.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl groups but referencesto individual alkenyl groups such as 2-butenyl are specific for thestraight chain version only. Unless otherwise stated, the term “alkenyl”advantageously refers to chains with 2 to 5 carbon atoms, preferably 3to 4 carbon atoms.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl groups but referencesto individual alkynyl groups such as 2-butynyl are specific for thestraight chain version only. Unless otherwise stated, the term “alkynyl”advantageously refers to chains with 2 to 5 carbon atoms, preferably 3to 4 carbon atoms.

In this specification, unless stated otherwise, the term “bond” may be asaturated or unsaturated bond.

In this specification, unless stated otherwise, the term “5 or 6membered heterocyclic group with one or two heteroatoms selectedindependently from O, S and N, which heterocyclic group may be saturatedor unsaturated” and “7 membered heterocyclic group with one or twoheteroatoms selected independently from O, S and N, which heterocyclicgroup may be saturated or unsaturated” includes both heteroaromaticrings and heterocyclic rings that are saturated. Examples of suchheterocyclic groups includes, but are not limited to, furyl, isoxazolyl,isothiazolyl, oxa-azepanyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl,imidazolidinyl, imidazolinyl, morpholinyl, piperazinyl, piperidyl,piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl or thiomorpholinyl.

In this specification, unless stated otherwise, the term “5 or 6membered saturated or unsaturated ring containing atoms selected from C,N, O or S” may be, but are not limited to, furyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl,imidazolinyl, morpholinyl, piperazinyl, piperidyl, piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,thiomorpholinyl, phenyl, cyclohexyl or cyclopentyl.

In this specification, unless stated otherwise, the term “5 or 6membered saturated heterocyclic group with one or two heteroatomsselected independently from O, S and N” may be, but are not limited to,imidazolidinyl, morpholinyl, piperazinyl, piperidinyl, piperidonyl,pyrazolidinyl, pyrazolidinyl, pyrrolidinyl, tetrahydropyranyl orthiomorpholinyl.

In this specification, unless stated otherwise, the term “5 or 6membered aromatic heterocyclic group with 1 to 3 heteroatoms selectedindependently from O, N and S” may be, but are not limited to, furyl,imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrazinyl, triazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl orthienyl.

In this specification, unless stated otherwise, the term halogeno may befluor, chlorine, bromine or iodine.

For the avoidance of any doubt, it is to be understood that when X² is,for example, a group of formula NR¹¹CO, it is the nitrogen atom besubstituted withing the R¹¹ group which is attached to the quinazolinering and the carbonyl (CO) group is attached to R¹⁰, whereas when X² is,for example, a group of formula CONR¹², it is the carbonyl group whichis attached to the quinazoline ring and the nitrogen atom be substitutedwithing the R¹² group is attached to R¹⁰. A similar convention appliesto the other two atoms X² linking groups such as NR¹⁴SO₂ and SO₂NR¹³.When X² is NR¹⁵ it is the nitrogen atom be substituted withing the R¹⁵group, which is linked to the quinazoline ring and to R¹⁰. An analogousconvention applies to other groups. It is further to be understood thatwhen X² represents NR¹⁵ and R¹⁵ is C₁₋₃alkoxyC₂₋₃alkyl it is theC₂₋₃alkyl moiety, which is linked to the nitrogen atom of X² and ananalogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that in acompound of formula I when R¹⁰ is, for example, a group of formulaC₁₋₅alkylX¹⁰C₁₋₅alkylR³⁴, it is the terminal C₁₋₅alkyl moiety, which islinked to X¹⁰, similarly when R¹⁰ is, for example, a group of formulaC₂₋₅alkenylR³⁴ it is the C₂₋₅alkenyl moiety, which is linked to X² andan analogous convention applies to other groups.

For the avoidance of any doubt, it is to be understood that when R³⁴carries a C₁₋₄aminoalkyl substituent it is the C₁₋₄alkyl moiety, whichis attached to R³⁴ whereas when R³⁴ carries a C₁₋₄alkylamino substituentit is the amino moiety, which is attached to R³⁹ and an analogousconvention applies to other groups.

For the avoidance of any doubt when X¹ is C₂₋₄alkanoyl it is thecarbonyl moiety, which is linked to the heteroaromatic oxindole groupand it is the alkyl moiety, which is linked to R⁴ and an analogousconvention applies to other groups.

The present invention relates to the use of compounds of formula I ashereinbefore defined as well as to the salts thereof. Salts for use inpharmaceutical compositions will be pharmaceutically acceptable salts,but other salts may be useful in the production of the compounds offormula I and their pharmaceutically acceptable salts.

Both organic and inorganic acids can be employed to form non-toxicpharmaceutically acceptable acid addition salts of the compounds of thisinvention.

A suitable pharmaceutically acceptable salt of the compounds of theinvention is, for example, an acid-addition salt, for example aninorganic or organic acid. In addition, a suitable pharmaceuticallyacceptable salt of the compounds of the invention is an alkali metalsalt, an alkaline earth metal salt or a salt with an organic base.

Some compounds of formula I may have chiral centres and/or geometricisomeric centres (E- and Z-isomers), and it is to be understood that theinvention encompasses all such optical, diastereoisomers and geometricisomers.

The invention also relates to any and all tautomeric forms of thecompounds of formula I.

Methods of Preparation

Intermediates

The intermediates used in the preparation of a compound of formula I asa free base or salts thereof, may be prepared by any process known to beapplicable to the preparation of chemically-related compounds. Suchprocesses include, for example, those illustrated in PCT application WO97/42187.

Methods of Preparation of End Products

Another object of the invention relates to processes for the preparationof compounds of formula I, Ib and Ic.

Process A describes the preparation of compounds of formula Ib, whereinR² is calkoxy, comprising of,

hydrolysis of a compound of formula Ia, wherein R² is C₁₋₆alkoxycarbonyland R¹, R³, m and n are as defined in general formula I, to obtain thecompound of formula Ib, wherein R² is carboxy and R¹, R³, m and n are asdefined in general formula I, may be carried out under acidic conditionsusing acids such as H₂SO₄, HCl or HBr in a suitable solvent e.g. water,ethanol, methanol or mixtures thereof and the reaction may occur between+20° C. and +100° C. or under basic conditions using bases such assodium hydroxide or potassium hydroxide in a suitable solvent e.g.water, ethanol, methanol or mixtures thereof and the reaction may occurat a temperature between +20° C. and +100° C.

Process B describes the preparation of compounds of formula Ic, whereinR² is R⁴X¹, comprising of

Amidation of a compound of formula Ib, wherein R² is carboxy and R¹, R³,m and n are as defined in general formula I, to obtain a compound offormula Ic, wherein R² is R⁴X¹ and X¹ is CONR⁵R⁶ and R¹, R³, R⁴, R⁵, R⁶,m and n are as defined in general formula I may be performed byactivation of a compound of formula Ib, wherein R² is carboxy, bytreating the compound with coupling reagents e.g.1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole hydrate or hydroxybenzimidazole,1,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole hydrate,1,1′-carbonyldiimidazole orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, or using an acyl halide reagent e.g. cyanuricchloride, oxalyl chloride, thionyl chloride orbromotrispyrrolidinophosphonium hexafluorophosphate, followed bytreatment with the appropriate amine with or without the presence ofN,N-dimethylaminopyridine, in a suitable solvent such asN,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, methylenechloride or chloroform at a reaction temperature between 0° C. and +80°C.

Alternatively, compounds of formula I, may be preparared by process C,comprising of

reacting a compound of formula II, wherein L¹ is a leaving group such asSCH₃ or a halogen e.g. chlorine or bromine and R³ and m are as definedin general formula I, with a compound of formula III, wherein R¹, R²,and n are as defined in general formula I.

Thus, the reaction of the process may be carried out in an appropriatesolvent such as an ether e.g. tetrahydrofuran or 1,4-dioxan, an aromatichydrocarbon solvent such as toluene, or a dipolar aprotic solvent suchas N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidin-2-one or dimethylsulphoxide and the reaction isconveniently effected at a temperature in the range of +10 to +150° C.,preferably in the range of +20 to +90° C. The reaction is advantageouslyeffected in the presence of a base. Such a base may be an organic aminebase such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine, N-methylmorpholine ordiazabicyclo[5.4.0]undec-7-ene, tetramethylguanidine, an alkali metal oralkaline earth metal carbonate or hydroxide such as sodium carbonate,potassium carbonate, calcium carbonate, sodium hydroxide or potassiumhydroxide. Alternatively, such a base is an alkali metal hydride such assodium hydride, or an alkali metal or alkaline earth metal amide such assodium amide, sodium bis(trimethylsilyl)amide, potassium amide orpotassium bis(trimethylsilyl)amide. When it is desired to obtain theacid salt, the free base may be treated with an acid, using aconventional procedure.

Intermediates

The present invention further relates to new compounds and the use ofthese compounds in the preparation of compounds of formula I as definedhereinbefore.

In one aspect of the invention the compound is a compound of formula II,

wherein:

-   L¹ is SCH₃;-   R³ is R¹⁰X²,    -   wherein X² is O, CH₂, S, SO, SO₂, NR¹¹CO, CONR¹², SO₂NR¹³,        NR¹⁴SO₂ or NR¹⁵ (wherein R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ each        independently are hydrogen, C₁₋₃alkyl or C₁₋₃alkoxyC₂₋₃alkyl),        or X² is a direct bond; and    -   R¹⁰ is C₁₋₅alkylX⁴R²¹ (wherein X⁴ is O or NR²⁶ (wherein R²¹ and        R²⁶ independently are hydrogen, C₁₋₃alkyl, cyclopentyl or        cyclohexyl)); and-   m is 1 or 2.

In one aspect of the invention the compounds2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid, methyl2-hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylateand compounds of formula II are used for the preparation of compounds offormula I.

EXAMPLES

The invention will now be illustrated by the following non-limitingExamples.

Example 1 Methyl2-hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylate

Sodium hydride (58 mg, 1.45 mmol, 60% in oil) was washed with petroleumether (3×5 mL) and dried in vacuo. The solid was suspended intetrahydrofuran (3 mL) and methyl 2-oxo-5-indolinecarboxylate (140 mg,0.73 mmol) in tetrahydrofuran (2 mL) and N-methylpyrrolidinone (2 mL)was added. The reaction mixture was stirred for 30 min at roomtemperature. A solution of 4-chloro-7-(2-methoxyethoxy)quinazoline (183mg, 0.77 mmol, described in WO 97/42187) in tetrahydrofuran (2 mL) andN-methylpyrrolidinone (1 mL) was added and the reaction mixture wasstirred for 1.5 h at room temperature. The solvent was removed in vacuoand 1 M hydrochloric acid was added. The precipitate formed was filteredoff and dried at 40° C. in vacuo over night to give 150 mg (99% yield)of the title compound as an orange solid: MS (AP+) m/z 394.2 (M⁺+1).

Example 22-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid

To a mixture of methyl2-hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylate(5.15 g, 13.1 mmol), methanol (100 mL) and water (50 mL) was addedaqueous sodium hydroxide (92 mL, 1 M) and the reaction mixture wasstirred at 40° C. over night. Methanol was removed in vacuo and thebasic aqueous layer was acidified with 1 M hydrochloric acid and stirredfor 30 min. The precipitate formed was filtered off, washed withhydrochloric acid (50 mL, 1 M) and water (2×50 mL) and dried in vacuo at50° C. over night. The crude product was stirred in methanol at roomtemperature over night. The solid was filtered off to give 4.23 g (85%yield) of the title compound as an orange solid: MS (AP+) m/z 380.3(M⁺+1).

Examples 3-11

General Method A

Stock solution A was prepared by dissolving2-hydroxy-3-[7-(2-methoxyethoxy)-quinazolin-4-yl]-1H-indole-5-carboxylicacid (2.0 g), (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(2.2 g) and hydroxybenzimidazole (1.54 g) in N-methylpyrrolidinone (160mL). Stock solution B was prepared by dissolvingN,N-dimethylaminopyridine (2.8 g) in N-methylpyrrolidinone (40 mL).

The amidation reaction was performed by adding solution A (8 mL,corresponding to2-hydroxy-3-[7-(2-methoxyethoxy)-quinazolin-4-yl]-1H-indole-5-carboxylicacid: 100 mg, 0.26 mmol, 1 eq;(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: 110 mg, 0.51mmol, 2.2 eq; hydroxybenzimidazole: 77 mg, 0.57 mmol, 2.2 eq) to areaction vessel containing the desired amine (0.4 mmol, 1.5 eq).Solution B (2 mL, corresponding to N,N-dimethylaminopyridine: 140 mg,1.14 mmol, 4.4 eq) was added and the resulting solution was stirred atroom temperature over night. The solvent was removed in vacuo to givethe crude product.

Example 33-[7-2(-Methoxyethoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylicacid (2-oxoazepan-3-yl)amide

The reaction was performed as described in method A using(3S)-3-aminoazepan-2-one (50 mg, 0.40 mmol). The crude product wastriturated with acetonitrile to give 109 mg (86% yield) of the titlecompound: MS (AP+) m/z 490.3 (M⁺+1).

Example 42-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid[3-(methylphenylamino)propyl]amide

The reaction was performed as described in method A usingN-(3-aminopropyl)-N-methylaniline (0.07 mL, 0.395 mmol). The crudeproduct was triturated with ethyl acetate. The solid was decanted andwashed with methanol to give 35 mg (26% yield) of the title compound: MS(AP+) m/z 526.3 (M⁺+1).

Example 52-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid [3-(1 -hydroxyethyl)phenyl]amide hydrochloride

The reaction was performed as described in method A using3-(1-hydroxyethyl)aniline (55 mg, 0.395 mmol). The crude product wastriturated with hydrochloric acid (1 M) to give 71 mg (55% yield) of thetitle compound: MS (AP+) m/z 499.2 (M⁺+1).

Example 62-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (1H-benzoimidazol-2-ylmethyl)amide

The reaction was performed as described in method A using2-(aminomethyl)benzimidazole dihydrochloride (88 mg, 0.395 mmol). Thecrude product was triturated with acetonitrile to give 28 mg (21% yield)of the title compound: MS (AP+) m/z 509.3 (M⁺+1).

Example 72-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (4-cyclohexylphenyl)amide hydrochloride

The reaction was performed as described in method A using4-cyclohexylaniline (69 mg, 0.395 mmol). The crude product wastriturated with hydrochloric acid (1 M), to give 110 mg (79% yield) ofthe title compound: MS (AP+) m/z 537.3 (M⁺+1).

Example 82-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid [2-(5 -methyl-1H-indol-3-yl)ethyl]amide hydrochloride

The reaction was performed as described in method A using5-methyltryptamine hydrochloride (83 mg, 0.395 mmol). The crude productwas triturated with hydrochloric acid (1 M), to give 101 mg (73% yield)of the title compound: MS (AP+) m/z 536.2 (M⁺+1).

Example 92-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid 4-sulfamoylbenzylamide

The reaction was performed as described in method A using4-(aminomethyl)benzenesulfonamide hydrochloride (0.06 mL, 0.395 mmol).The crude product was triturated with methanol and the solid wasre-crystallised from hot methanol to give 72 mg (51% yield) of the titlecompound: MS (AP+) m/z 548.3 (M⁺+1).

Example 102-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (4,4-diethoxybutyl)amide

The reaction was performed as described in method A using4,4-diethoxybutylamine (0.07 mL, 0.395 mmol). The crude product waswashed with acetone and the solid was washed with hot methanol to give10 mg (7.4% yield) of the title compound: MS (AP+) m/z 523.3 (M⁺+1).

Example 112-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (1-benzylpiperidin-4-yl)amide hydrochloride

The reaction was performed as described in method A usingbenzyl-4-piperidylamine (0.08 mL, 0.395 mmol). The crude product wastriturated with acetone. The formed solid was stirred in hydrochloricacid (1 M), filtered and dried in vacuo to give 39 mg (27% yield) of thetitle compound: MS (AP+) m/z 552.4 (M⁺+1).

Pharmaceutical Compositions

According to one aspect of the present invention there is provided apharmaceutical composition comprising a compound of formula I, as a freebase or salts thereof, for use in prevention and/or treatment ofdementia related diseases, Alzheimer's Disease and conditions associatedwith glycogen synthase kinase-3 and other conditions listed below.

The composition may be in a form suitable for oral administration, forexample as a tablet, pill, syrup, powder, granule or capsule, forparenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion) as a sterile solution,suspension or emulsion, for topical administration as an ointment, patchor cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using pharmaceutically carriers or diluents.

Suitable daily doses of the compounds of formula I in the treatment of amammal, including man, are approximately 0.01 to 250 mg/kg bodyweight atperoral administration and about 0.001 to 250 mg/kg bodyweight atparenteral administration. The typical daily dose of the activeingredients varies within a wide range and will depend on variousfactors such as the relevant indication, the route of administration,the age, weight and sex of the patient and may be determined by aphysician.

Medical Use

Surprisingly, it has been found that the compounds defined in thepresent invention, as a free base or salts thereof, are useful intherapy. The compounds of the present invention are well suited forinhibiting glycogen synthase kinase-3 (GSK3). Accordingly, the compoundsof the present invention are expected to be useful in the preventionand/or treatment of conditions associated with glycogen synthasekinase-3 activity, i.e. the compounds may be used to produce aninhibitory effect of GSK3 in mammals, including man, in need of suchprevention and/or treatment.

GSK3 is highly expressed in the central and peripheral nervous systemand in other tissues. Thus, it is expected that compounds of theinvention are well suited for the prevention and/or treatment ofconditions associated with glycogen synthase kinase-3 in the central andperipheral nervous system. In particular, the compounds of the inventionare expected to be suitable in the manufacture of a medicament for theprevention and/or treatment of dementia related diseases and Alzheimer'sDisease.

The dementia related diseases are selected from the group consisting ofFrontotemporal dementia Parkinson's Type, Parkinson dementia complex ofGuam, HIV dementia, diseases with associated neurofibrillar tanglepathologies, predemented states, vascular dementia, dementia with Lewybodies, Frontotemporal dementia and dementia pugilistica.

The compounds of the invention are also expected to be suitable in themanufacture of a medicament for the prevention and/or treatment ofamyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome,Huntington's Disease, Parkinson's Disease, postencephelaticparkinsonism, progressive supranuclear palsy, Pick's Disease,Niemann-Pick's Disease, stroke, head trauma and other chronicneurodegenerative diseases, Bipolar Disease, affective disorders,depression, schizophrenia, cognitive disorders, hair loss andcontraceptive medication.

The compounds of the invention are further expected to be suitable inthe manufacture of a medicament for the prevention and/or treatment ofMild Cognitive Impairment, Age-Associated Memory Impairment, Age-RelatedCognitive Decline, Cognitive Impairement No Dementia, mild cognitivedecline, mild neurocognitive decline, Late-Life Forgetfulness, memoryimpairment and cognitive impairment and androgenetic alopecia.

The present invention relates also to the use of a compound of formula Ias defined hereinbefore, in the manufacture of a medicament for theprevention and/or treatment of conditions associated with glycogensynthase kinase-3.

In the context of the present specification, the term “therapy” alsoincludes “prevention” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention also provides for a method of prevention and/or treatmentof dementia related diseases, Alzheimer's Disease and conditionsassociated with glycogen synthase kinase-3 and other conditions listedabove comprising administrering to a mammal, including man, in need ofsuch prevention and/or treatment a therapeutically effective amount of acompound of formula I, as hereinbefore defined.

Non-Medical Use

In addition to their use in therapeutic medicine, the compounds offormula I as a free base or salts thereof, are also useful aspharmacological tools in the development and standardisation of in vitroand in vivo test systems for the evaluation of the effects of inhibitorsof GSK3 related activity in laboratory animals such as cats, dogs,rabbits, monkeys, rats and mice, as part of the search for newtherapeutics agents.

Pharmacology

Determination of ATP Competition in Scintillation Proximity GSK3β Assay.

GSK3β Scintillation Proximity Assay.

The competition experiments were carried out in duplicate with 10different concentrations of the inhibitors in clear-bottom microtiterplates (Wallac, Finland). A biotinylated peptide substrate,Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO₃H₂)-Pro-Gln-Leu(AstraZeneca, Lund), was added at a final concentration of 1 μM in anassay buffer containing 1 mU recombinant human GSK3β (Dundee University,UK), 12 mM morpholinepropanesulfonic acid (MOPS), pH 7.0, 0.3 mM EDTA,0.01% β-mercaptorethanol, 0.004% Brij 35 (a natural detergent), 0.5%glycerol and 0.5 μ g BSA/25 μl. The reaction was initiated by theaddition of 0.04 μCi [γ-³³P]ATP (Amersham, UK) and unlabelled ATP at afinal concentration of 1 μM and assay volume of 25 μl. After incubationfor 20 minutes at room temperature, each reaction was terminated by theaddition of 25 μl stop solution containing 5 mM EDTA, 50 μM ATP, 0.1%Triton X-100 and 0.25 mg streptavidin coated Scintillation ProximityAssay (SPA) beads (Amersham, UK). After 6 hours the radioactivity wasdetermined in a liquid scintillation counter (1450 MicroBeta Trilux,Wallac). The inhibition curves were analysed by non-linear regressionusing GraphPad Prism, USA. The K_(m) value of ATP for GSK30, used tocalculate the inhibition constants (K_(i)) of the various compounds, was20 μM.

The following abbreviations have been used:

-   ATP Adenosine Triphophatase-   BSA Bovin Serum Albumin-   EDTA Ethylenediaminetetraacetic acid-   GSK3 Glycogen synthase kinase 3-   MOPS Morpholinepropanesulfonic acid-   SPA Scintillation Proximity Assay    Results

Typical K_(i) values for the compounds of the present invention are inthe range of about 0.001 to about 10,000 nM. Other values for K_(i) arein the range of about 0.001 to about 1000 nM. Further values for K_(i)are in the range of about 0.001 nM to about 300 nM.

1. A compound which is 3-[7-2(-Methoxyethoxy)quinazolin-4-yl]-2-oxo-2,3-dihydro-1H-indole-5-carboxylic acid(2-oxoazepan-3-yl)amide,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid [3-(methylphenylamino)propyl]amide,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid [3-(1-hydroxyethyl)phenyl]amide,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (4-cyclohexylphenyl)amide,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (4,4-diethoxybutyl)amide,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (1H-benzoimidazol-2-ylmethyl)amide,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid [2-(5-methyl-1H-indol-3-yl)ethyl]amide,2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid 4-sulfamoylbenzylamide or2-Hydroxy-3-[7-(2-methoxyethoxy)quinazolin-4-yl]-1H-indole-5-carboxylicacid (1-benzylpiperidin-4-yl)amide, as a free base or a salt thereof.